We have generated two independent lines of transgenic (Tg) mice (lines C3- 3 and E1-2) that express mutant humanized amyloid precursor protein (APP) (Mo/Hu-APPswe) at levels sufficient to induce beta-amyloid (Abeta) deposition between 20 and 24 months of age. These animals have been mated C57BL/6J mice for ten generations to obtain congenic animals (99.99%). In Project 1, we propose to conduct behavior tests (Morris water maze, eight-arm radial maze, and Y-maze) designed to examine the cognitive abilities of our congenic/Tg Mo/Hu-APPswe mice. Following behavioral testing, each cohort (6-, and 14-, 22- and 28 months of age) will be humanely sacrificed to provide tissues for detailed neuropathological/neurochemical evaluations (Project 2). Together, these studies will determine whether changes in cognitive performance correlate with specific neuropathological/neurochemical evaluations (Project 2). Together, these studies will determine whether changes in cognitive performance correlate with specific neuropathological/neurochemical abnormalities. Importantly, our planned study will, for the fist time, behaviorally characterize mutant APP Tg mice that are congenic on a single inbred strain background and will be the first to confirm findings of two independent lines of mice that express similar levels of mutant APP and develop Abeta deposits at similar ages. To explore the relationship between Abeta deposition and develop Abeta deposits and associated abnormalities at younger ages. These cohorts will be tested blindly and then sacrificed for neuropathological/neurochemical analysis (data provided by Project 2). Finally, a third line of Mo/Hu-APPswe mice (line Q2-2), which expresses the transgene at levels slightly less than required to induce Abeta deposition, will be behaviorally and neuropathologically/neurochemically analyzed. Our planned behavioral characterization of the mice, together with the neuropathological/neurochemical studies proposed in Project, will allow us to determine (with assistance in statistical analysis from Core B) the influence of APP hyper-expression, Abeta peptide synthesis, and Abeta deposition on the cognitive abilities of mice.